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Nicotine consumption QTL: Fine mapping, selective breeding and sequencing

尼古丁消耗QTL：精细定位、选育和测序

基本信息

批准号：
9086336
负责人：
RICHARD A RADCLIFFE
金额：
$ 27.7万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Genetics clearly contributes to individual risk for nicotine dependence in humans and variations in nicotine sensitivity in experimental animals. In mice, several behavioral and physiological responses to nicotine have been demonstrated to be influenced by genetics. However, none of the specific genes that contribute to the genetic influence on nicotine sensitivity in mice have been identified. These genes remain an untapped source of information that almost certainly will improve our understanding of what drives individual differences in nicotine sensitivity. For example, the recent discovery that variants in human CHRNA5 are associated with risk for nicotine dependence in humans led to follow-up studies in rodents which not only helped to identify a specific neuronal pathway critical for controlling the level of nicotine consumption, but also demonstrated that this gene impacts individual differences in nicotine self-administration not by increased sensitivity to the reinforcng effects of nicotine at low doses but rather a lack of the loss of reinforcement at aversive doses. This is just one of many examples where the identification of a gene that contributes to individual variability in a phenotypic measure can lead to significant insights into the underlying biology of the measure. We previously have mapped chromosomal regions that harbor genes or genes that contribute to individual differences in oral nicotine intake in mice and it is the goal f this project to follow up this initial finding to identify the genes that contribute to variation i nicotine intake. For this, we will again map chromosomal regions that impact nicotine intake but this time in a panel of mice that will allow us to define with much greater precision the regions i the genome that harbor genes that impact nicotine intake. We will follow this up with selective breeding to produce lines of mice that differ in nicotine intake. The selection process should produce mouse lines that are enriched for alleles that are involved in increasing or decreasing nicotine intake. Finally, we will perform whole genome sequencing on the selected lines. We will use these sequencing data to establish whether the chromosomal regions identified through mapping are enriched through the selection process and to identify all variants within the region. We also will analyze the sequence data for other potential chromosomal regions that have been enriched through selection for nicotine consumption. This multi-tiered approach should allow us to substantially narrow the search for variants that influence nicotine intake and potentially lead to the identification of causal variants (functional variants that contribute to individual variabiity in nicotine consumption).

描述（由申请方提供）：遗传学明显有助于人类尼古丁依赖的个体风险和实验动物尼古丁敏感性的变化。在小鼠中，已证明对尼古丁的几种行为和生理反应受遗传学影响。然而，没有一个特定的基因，有助于遗传影响尼古丁敏感性的小鼠已被确定。这些基因仍然是一个未开发的信息来源，几乎可以肯定地说，这将提高我们对尼古丁敏感性个体差异的理解。例如，最近发现人类CHRNA5的变异与人类尼古丁依赖的风险相关，导致在啮齿动物中进行了后续研究，这不仅有助于确定对控制尼古丁消耗水平至关重要的特定神经元通路，但也证明了这个基因影响尼古丁自身的个体差异，这不是通过增加对低剂量尼古丁的增强作用的敏感性来实现的，而是通过在厌恶剂量下缺乏增强作用来实现的。这只是许多例子中的一个，在表型测量中鉴定出有助于个体变异性的基因可以导致对潜在的基因的重要见解。测量的生物学。我们之前已经绘制了染色体区域，这些区域含有基因或导致小鼠口服尼古丁摄入量个体差异的基因，本项目的目标是跟踪这一初步发现，以确定导致尼古丁摄入量变化的基因。为此，我们将再次绘制影响尼古丁摄入量的染色体区域，但这次是在一组小鼠中，这将使我们能够更精确地定义基因组中含有影响尼古丁摄入量的基因的区域。我们将通过选择性繁殖来生产尼古丁摄入量不同的小鼠品系。选择过程应该产生富含参与增加或减少尼古丁摄入的等位基因的小鼠品系。最后，我们将对选定的品系进行全基因组测序。我们将使用这些测序数据来确定通过作图鉴定的染色体区域是否通过选择过程富集，并鉴定该区域内的所有变体。我们还将分析其他潜在染色体区域的序列数据，这些区域通过选择尼古丁消费而富集。这种多层次的方法应该使我们能够大大缩小对影响尼古丁摄入量和潜在铅的变异的搜索范围鉴定因果变异体（导致尼古丁摄入量个体差异的功能变异体）。